Cyclin-dependent kinases (CDKs) are the catalytic subunits of a large family of serine/threonine protein kinases. Activation of specific CDKs is required for the appropriate progression through a given stage of the cell cycle and into the next stage in the cell cycle. Regulation of CDK activity is pivotal for the correct timing of cell cycle progression and CDK activity is tightly regulated at many levels, including complex formation with cyclins and CDK inhibitors (CDKI), in particular CIP/KIP and INK-type CDKIs, as well as phosphorylation and dephosphorylation. Central to the activation of a given CDK is the requirement for association with cyclins and phosphorylation at a threonine residue in the activation loop (T-loop). Cyclins are synthesized and degraded during the cell cycle, so that activation of a particular CDK occurs only when its cyclin partner(s) becomes available. Additionally, many CDKs require phosphorylation of a threonine residue in the activation loop (T-loop) for their activation. In the case of CDK1, CDK2, CDK4 and CDK6 T-loop phosphorylation is mediated by the CDK activating kinase (CAK).
Deregulation of CDK activity forms an important part of many disease states, generally through elevated and/or inappropriate activation, as CDKs are infrequently mutated. Important mechanisms of CDK deregulation include cyclin overexpression. For example, the cyclin D1 gene is frequently amplified in cancer (Fu et al. Endocrinology 145: 5439-5447 (2004)). CDKI expression is frequently lost, for example, through mutational or epigenetic alterations in genes encoding INK4, CIP or KIP CDKIs in cancer (Malumbres and Barbacid, Nature Reviews Cancer 1, 223-231 (2001)).
CDKs are important targets for the design of drugs with antimimotic, antineurodegenerative, antiviral and antitumor effects. Recently, a class of CDK inhibitors having a pyrazolo[1,5-α]pyrimidine skeleton has been developed. These compounds show a high potency for inhibiting CDK2, and in some cases were shown to inhibit the growth of human colon tumor cells (D. S. Williamson et al., Bioorg. Med. Chem. Lett., 15, 863-867 (2005)).
International Publication Nos. WO 04/022561 and WO 05/077954 to Guzi et al. describe certain pyrazolo[1,5-α]pyrimidine compounds which can be used as CDK inhibitors.
International Publication No. WO 08/027,220 to Chen et al. discloses processes for the preparation of certain (3-alkyl-5-piperidin-1-yl-3,3α-dihydro-pyrazolo [1,5-α]pyrimidin-7-yl)-amino derivatives which are described as useful as CDK inhibitors.
International Publication No. WO 08/151,304 to Emory University and Imperial College of Science and Technology describes certain pyrazolo[1,5-α]pyrimidine compounds for the inhibition of cyclin-dependent kinases and process of preparing these compounds using certain protecting groups and coupling catalysts at high temperatures.
There remains a need for improved processes for the preparation of amino-substituted pyrazolo[1,5-α]pyrimidine compounds that are useful as CDK inhibitors. In particular, a process suitable for large scale production of the compounds is needed. It is therefore an object of the invention to provide improved processes that allow large scale production of such compounds at low temperatures using ingredients that are available at reduced costs and with reduced toxicity.